Safety and regulatory concerns in �Psychedelic research

ACS National Meeting

August 19^th 2024

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Research in Psychedelics

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Nichols, D. E.; Barker, E. L. Pharmacological Reviews, 2016, 68 (2) 264-355

“Psychedelics (serotonergic hallucinogens) are powerful psychoactive substances that alter perception and mood and affect numerous cognitive processes.”

DEA classifies psychedelics as Schedule 1

Cannabis legalization in WA and CO (2012)

 Rohrabacher–Farr amendment prohibits Federal prosecution of people complying with state cannabis laws (2014)

The Psychedelic Renaissance

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“The use of psychedelics as medicines is perhaps one of the most exciting developments in neuropsychiatry given that these drugs appear to produce both rapid and sustained therapeutic effects across multiple neuropsychiatric disorders, including depression, post-traumatic stress disorder (PTSD), and substance use disorder (SUD).”

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ACS Pharmacol. Transl. Sci. 2021, 4, 2, 413–415

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Some Tryptamines of Pharmacological Interest

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These are all really simple compounds!

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Most of the compounds on this slide are scheduled or controlled!

Safety Overview

Basic Chemical Safety

Responsible Handling

Trusting your Personnel

Responsible Handling

Very subtle changes lead to dramatic effects –

Be extremely careful about exposure!

(with perhaps 15 mg, smoked) I took a hit from the pipe with five-methoxy in it, and after the 8 to 1 0 seconds it took to carry the chemical to my brain I remember starting to fall over from my sitting position. My normal physical perceptions dissolved away from my awareness. My ears started to ring and I started to float off. I was acutely aware of a certain resonation of my aural perception, an electrical buzzing that fluctuated in synch with my visual perception.

(10 mgs, smoked with peppermint leaves) After a few minutes a high feeling with some dizziness, intense heartbeat, trembling, anxiety, restlessness, cold sweating, paleness and weak belly cramps. There were some visions I could not concentrate because of the strong side-effects. I felt sick, went to bed and was very glad when the effects disappeared after about one and a half hour.

What I saw can only be described as a fantastically subtle multicolored phosphene, completely filling every area visually available. I say it in this way because I was simultaneously losing contact with my body, I could not tell if my eyes were open or shut, although I initially had the feeling that they were darting back and forth, from side to side. These feelings and sensations built up in intensity very quickly, a matter of seconds: I can remember this feeling of building intensity up to a point, and then I was not there in my body or in time. In the 10 to 15 minutes that my body was under the influence of the drug my mind was completely referenceless, there was no way for my consciousness to limit or gauge the stimuli my being was barraged with. I remember switching to a perception where the endless and intricate phosphene was love and the energy of light. I called upon those forces within my being to realign and submit, to let go of all the cogent fears and just exist ... and that innate decision saved me a lot of psychic damage. What is most outstanding about the way it feels is an inability to judge in any way, by any method of the mind ... it is unconquerable, as deep and profound as a totally unconditional love that is life. What a trip, huh?

Just imagine that happening by accident while in the lab!

Shulgin ‘Potency’ Scale

• MINUS, n. (-) On the quantitative potency scale (-, ±, +, ++, +++), there were no effects observed.

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• PLUS/MINUS, n. (±) The level of effectiveness of a drug that indicates a threshold action. If a higher dosage produces a greater response, then the plus/minus (±) was valid. If a higher dosage produces nothing, then this was a false positive.

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• PLUS ONE, n. (+) The drug is quite certainly active. The chronology can be determined with some accuracy, but the nature of the drug's effects are not yet apparent.

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• PLUS TWO, n. (++) Both the chronology and the nature of the action of a drug are unmistakably apparent. But you still have some choice as to whether you will accept the adventure, or rather just continue with your ordinary day's plans (if you are an experienced researcher, that is). The effects can be allowed a predominant role, or they may be repressible and made secondary to other chosen activities.

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• PLUS THREE, n. (+++) Not only are the chronology and the nature of a drug's action quite clear, but ignoring its action is no longer an option. The subject is totally engaged in the experience, for better or worse.

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• PLUS FOUR, n. (++++) A rare and precious transcendental state, which has been called a "peak experience," a "religious experience," "divine transformation," a "state of Samadhi" and many other names in other cultures. It is not connected to the +1, +2, and +3 of the measuring of a drug's intensity. It is a state of bliss, a participation mystique, a connectedness with both the interior and exterior universes, which has come about after the ingestion of a psychedelic drug, but which is not necessarily repeatable with a subsequent ingestion of that same drug. If a drug (or technique or process) were ever to be discovered which would consistently produce a plus four experience in all human beings, it is conceivable that it would signal the ultimate evolution, and perhaps the end, of the human experiment.

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For an idea about how different ”different” can be:

Regulatory Requirement Overview

DEA Drug Scheduling System

The DEA separates license applications into “Schedule I” and “everything else”

Regulatory Requirement Overview

2) Obtain authorization from your Institution – this can vary wildly!

3) Obtain a Board of Pharmacy license from your State licensing board for all required Schedules (I - V) – this can vary wildly!

4) Complete the DEA application form online for the required Scheduled compounds – start to finish, this can take up to six months!

1) Ensure your lab is set up to safely handle and store (!) the required compounds

5) All compounds purchased from suppliers must be accounted for

(to the mg) in a use log which is auditable by any of the above

Purchasing from a Supplier

DEA Form 222 – Treated like bearer bonds, but for drugs

Trusting your Personnel

All personnel working with Scheduled compounds must be cleared by the DEA

But what about unscheduled tryptamines? You have to be sure you can trust all people working with compounds that might be psychoactive!

It’s about Ethics in Clinical Trials

The Editors have retracted this article after they were informed of protocol violations amounting to unethical conduct at the MP4 study site by researchers associated with this project. The authors have subsequently confirmed that they were aware of these violations at the time of submission of this article, but did not disclose this information to the journal or remove data generated by this site from their analysis. Additionally, the authors also did not fully declare a potential competing interest. Several of the authors are affiliated with either the Multidisciplinary Association for Psychedelic Studies (MAPS) or MAPS Public Benefit Corporation (MAPS PBC), a subsidiary that is wholly owned by MAPS. As is stated in the Funding declaration, MAPS fully funded and provided the MDMA that was used in this trial, and MAPS PBC organised the trial.

“In 2019, MAPS posted a public announcement of ethical violations by investigators who had been involved in a MAPS-sponsored clinical trial of MDMA. A female participant in a study submitted complaints in 2018 about two therapists in Canada after one of the therapists “engaged in a sexual relationship with the participant,” MAPS said in an updated statement in 2022.

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The two therapists verbally confirmed to MAPS that the “sexual relationship” occurred and were banned in 2018 from “all MAPS-related activities and from becoming providers of MAPS-affiliated MDMA-assisted therapy if the treatment is approved,” the statement said.”

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Deidre McPhillips and Carma Hassan, CNN (August 13, 2024)

Good luck with your drugs!

The research area is very active, but also very visible – there are knock-on effects for everyone in the field when things go awry!

Acknowledgements

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Stacie DeBoer

Veronica Shuger

Dominic D’Agostino

Ethan Johnson

Quetzalli Penaloza-Orozco 

Kelly Van Damme  

Allyson Cardine